Synthesis of steroids



United States Patent W 3,288,810 SYNTHESIS OF STEROIDS Gerald W. Krakower, Elizabeth, and Hilda A. Schwartz, Highland Park, N.J., assigmors, by mesne assignments, to E. R. Squibb & Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed May 20, 1965, Ser. No. 457,499 4 Claims. (Cl. 260343.2)

This invention relates to and has as its object the provision of new physiologically active steroids, novel methods for their production and new intermediates useful in said preparation. More particularly, this invention relates to the preparation of compounds of the formula wherein R is hydrogen and R is hydroxy or acyloxy; and together R? and R is 0x0 (0 The preferred acyl and acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic, propionic, butyric and tert-pentanoic acid), the lower alkenoic acids, the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and fl-phenylpropionic acid), the cycloalkane carboxylic acids and the cycloalkene carboxylic acids.

The final products of this invention are physiologically active steroids which possess uterotrophic activity and may be used in the treatment of such conditions as menstrual disorders, being formulated for such administration in the manner and/ or dosage as determined by the respective compound involved and the requirements of the patient.

The final compounds of this invention may be prepared according to the processes of this invention which may be represented by the following equations wherein R" and R" are as hereinbefore defined:

In the first step of the novel process of this invention, the starting materials (Compounds A) are reduced as by treatment with a reducing agent, for example, an alkali metal borohydride, such as sodium borohydride, to yield the 1l-hydroxy-16 unsubstituted derivatives thereof. The starting materials (Compounds A) which may be employed in the practice of this invention are those which 3,2883% Patented Nov. 29, 1966 may be prepared by reducing 'a compound having the wherein R is acyloxy and R" and R' are as defined herein with a reducing agent, such as alkali metal borohydride, e.g., sodium borohydride to yield ll-hydroxy- 16-unsubstituted derivatives.

To obtain the ll-acylated starting compounds of this invention, the corresponding ll-hydroxylated derivatives may be acylated under acetic conditions, as by treatment with acid, acid anhydride, and toluene sulphonic acid. The 3-hydroxy compounds may be mono-acylated as by treatment with an acylating agent, for example, acid anhydride or acyl halide in the presence of an organic base, .such as collidine or pyridine, to yield the 3-acylated derivatives. The processes for preparing the starting materials of the instant invention are more fully set forth in a prior application, Serial No. 419,231, filed December 17, 1964, now abandoned, in the names of Gerald W. Krakower and Hilda Anne Schwartz.

' The 3,11-dihydroxy compounds are first mono-acylated as by treatment with an acylating agent, for example, acid anhydride' or acyl halide, in the presence of an organic base, such as collidine or pyridine, to yield the 3-acylatedll-hydroxy derivatives.

The 3-acylated-11-hydroxy derivatives may then be dehydrated :as by treatment with a dehydrating agent, for example, an inorganic acid halide such as thionyl chloride in an organic base, such as collidine or pyridine to yield the 3-acyloxy-9,l1-dehydro novel final products of the instant invention.

In addition, the 3-acyloxy-9,11-dehydro final products may be further treated to yield the other novel final products of this invention. The 3-acyloxy-9,11-dehydro compounds may be hydrolyzed as by treatment with an alcoholic alkali metal hydroxide, for example, ethanolic potassium hydroxide to yield the 3-hydroxy-9,11-dehydro novel final products of this invention.

The 3-hydroxy-9,1l-dehydro final products may then be oxidized as by treatment with an oxidizing agent, such as chromic acid to yield the 3-keto-9,11-dehydro final products of this invention.

The invention may be further illustrated by the followv ing examples:

A suspension of 250 mg. of 3u,16B-diacetoxy-4u,8,14- trimethyl 17 oxa D homo-l8-nor-5u,8a,9fi,l3a,1413- androstane-11,17a-dione in 25 ml. of absolute ethanol is treated with mg. of sodium borohydride, and stirred at room temperature. After ten minutes the substrate dissolves and after seventy-five minutes the reaction mixture is acidified with glacial acetic acid. The solvent is evaporated and the residue is taken up in ethyl acetate. After washing with saturated salt solution, drying and evaporation of the solvent, 210 mg. of crystalline material is obtained. Two recrystallizations from methanol give 84 mg. of analytically pure 3a-acetoxy-lla-hydroxy- 4a,8,14 trimethyl 17-oxa-D-homo-18-nor-5a,8a,9/3,13a,

Example 2.3a-acet0xy-4a,8,14 trimethyl 17 oxw-D- hm0-18-n0r u,8a,9{3,13a,14 3 androsrane 11,17adione A solution of 48 mg. of 3u-acetoxy-1la-hydroxy-4a,8, 14-trimethyl-17-oxa-D-homo-l8 nor 5a,8u,9fi,130z,l413- androstane-l'la-one in 2 -ml. of acetone is treated with an excess of chromic acid-sulfuric acid reagent. After five minutes at room temperature, the excess chromic acid is reduced with methanol and the solution diluted with water. The solvent is evaporated and the aqueous suspension is extracted with methylene chloride. The methylene chloride solution .is Washed with saturated salt solution, dried and evaporated to give 34 mg. of material. Recrystallization from methanol gives 20 mg. of 3a-acetoxy-4a,8,14-trin1ethyl 17 oxa D-homo-18-nor- 5u,8a,9fl,13m,l4B-androstane-l1,17a-dione, M.P. 214- 215 C., [@1 9 -9.4.

Analysis.Calcd for C H O C, 70.74; H, 8.78. Found: C, 70.78; H, 8.74.

Example 51-35,] 1 a-dihydroxy-4 (1,8,1 4-trz'methyl-1 7-0xa- D-homo-l 8-n0r-5a,8a,9/3,1 3a,14;i-andr0stane-1 7a-0ne A suspension of 400 mg. of 16 3-acetoxy-4u,8,14-trimethyl 17 oxa D homo 18 n0I5u,8a,9B,13m,14-,B- androstane-3,1l,l7a-trione in 40 ml. of absolute ethanol is treated with 300 mg. of sodium borohydride and stirred at room temperature for three hours. The reaction is then Worked up as described in Example 1 to give 373 mg. of crude 33,1la-dihydroxy-4a,8,14-trimethyl-17- oxa-D-homo-lS-nor 5a,8a,9,8,13a,143 androstane-l7aone. Recrystallization from methanol gives 79 mg., 279-284 C. The analytical sample has M.P. 283- 284 C.

Analysis.Calcd for C H 0 C, 71.96; H, 9.78. Found: C, 72.00; H, 9.60.

3,6,11a-dihydroxy-4u,8,14 trimethyl-17-oxa-D-homo- 18-I1Of-5a,8oc,9fi,l30:,145-3I1df08tfl116-1'Z3-0118 is dissolved in a mixture of pyridine-acetic anhydride and left overnight at room temperature. After addition of water the mixture is evaporated and the residue recrystallized from methanol to give 35-acetoxy-1lot-hydroxy-4ix,8,14trimethyl 17 oxa D homo 18 nor-5u,8m,9;8,13a,14flandrostane-l7a-one, M.P. 197l98 C., [at] 13.5 (chloroform).

Analysis.-Calcd for C H O C, 70.37; H, 9.24. Found: C, 70.51; H, 9.18.

Similarly, following the procedure of Example 4, but substituting equivalent amounts of other acylating agents, for example, propionyl anhydride or benzoyl chloride for acetic anhydride, there is obtained the respective 3-propionate and S-benzoate derivatives.

Example 5.--3fi-acet0xy 4oc,8,14 trimethyl 17-oxa-D- homo 18 nor 5a,8a,13a,14fi androst -9(11)-ene- 17a-0ne A solution of 50 mg. of thionyl chloride in 0.5 ml. of pyridine is added to 50 mg. of 3,8acetoxy-|1lu-hydroxy- 4a,8,14-tr-imethyl-17-oxa D homo-18-nor-5a,8a,918,l3a, 14(3-androstane-17a-one in 1 ml. of pyridine cooled to 20 C. The reaction mixture is kept at 0 C. for 30 minutes and then quenched with water and extracted with ethyl acetate. The ethyl acetate solution is washed with 5% hydrochloric acid and saturated sodium chloride solution, dried and evaporated to give 43 mg. of crude material. Recrystallization from methanol .gives 22 mg. of 3B-acetoxy-4a,8,l4-trimethyl-l7 oxa-D-homo-lS-nof- 50,8ot,l30t,14-B-&Ildl'OSt-9(11)-ene-17a-OI16, M.P. 255 256 C., [ml -30.2 (chloroform).

Analysis.Calcd for C H O C, 73.76; H, 9.15. Found: C, 73.64; H, 9.12.

A solution of 81 mg. of 3fi-acetoxy-4a8,14-trimethyl- 17-oxa-D-homo-18 nor 5a,8u,13u-14B androst-9(11)- ene-l7a-one, in 25 ml. of 5% ethanolic potassium hydroxide is left overnight at room temperature. The solu tion is then acidified with 20% sulfuric acid, diluted with water and the solvent evaporated. The aqueous suspension is extracted with ethyl acetate and washed with saturated salt solution, dried and evaporated to give crude 3 3 hydroxy-4a,8,14-trimethyl-l7-oxa-D-homo-18- nor-5a,8a,l3a,l4fi-androst-9(11)-ene-17a-one.

Oxidation of the material of Example 6 with chromic acid-sulfuric acid as described in Example 2 gives crude 4a,8,14-trimethyl-1 7-oxa-D homo-18-nor-5a,8a,13a,14,6- androst-9'( l l -ene-3, 17-a-dione.

The invention may be variously otherwise em-bodied within the scope of the appended claims.

What is claimed is:

1. A compound of the formula:

wherein R is hydrogen; R" is selected from the group consisting of hydroxy and acyloxy, wherein the acyl radical is of a hydrocarbon carboxylic acid of less than twelve carbon atoms; and together R and R" is oxo 2. 35-acetoxy-4a,8,14-trimethy1-17-oxa D homo-18- ROI-5058a,13a,14fland1OSt-9( 1 1) -ene-17a-one.

4. 4a,8,14-trimethyl-17 oxa D homo-18-nor-5a,8o:, 13a,l4B-androst-9(1 l )-ene-3,17a-dione.

No references cited.

JOHN D. RANDOLPH, Primary Examiner.

WALTER A. MODANCE, J. A. PATTEN,

Assistant Examiners. 

1. A COMPOUND OF THE FORMULA: 